Anti-inflammatory effects of melatonin: A systematic review and meta-analysis of clinical trials.

Chronic inflammation contributes to multiple diseases including cardiovascular diseases, autoimmune disorders, metabolic disorders, and psychiatric conditions. Melatonin, a hormone responsible for circadian rhythm, plays a complex role within the immune system, including having an anti-inflammatory effect. While there are numerous animal studies demonstrating this effect, few human clinical trials have been conducted. This systematic review of clinical trials examined whether exogenous melatonin reduces levels of inflammatory markers in humans. We searched PubMed, Embase, Cochrane Library, Scopus, and PsycINFO, and the references of the identified articles for randomized and non-randomized placebo-controlled trials. Data were extracted from the articles and meta-analyses were conducted using a random effects model to calculate standardized mean differences (SMDs, i.e., Cohen's d). From an initial search result of 4548 references, 31 studies met the inclusion criteria and were included involving 1517 participants. Melatonin had significant anti-inflammatory effects on interleukin (IL)-1 (SMD -1.64; 95% confidence interval [CI] -2.86, -0.43; p = 0.008), IL-6 (-3.84; -5.23, -2.46; p < 0.001), IL-8 (-21.06; -27.27, -14.85; p < 0.001), and tumor necrosis factor (TNF) (-1.54; -2.49, -0.58; p = 0.002), but not on C-reactive protein (CRP) (-0.18; -0.91, 0.55; p = 0.62). Trimming outlier studies with large effect sizes eliminated publication bias, and summary effect sizes were significant for IL-1 (SMD -1.11; 95% CI -1.90, -0.32; p = 0.006), IL-6 (-1.91; -2.98, -0.83; p = 0.001), and IL-8 (-13.46; -18.88, -8.04; p < 0.001), but not for TNF (-0.45; -1.13, 0.23; p = 0.19). Exogenous melatonin reduced levels of inflammatory markers and may be useful for prevention and adjuvant treatment of inflammatory disorders. Melatonin is safe with few side effects, which makes it an excellent agent for prevention of inflammatory disorders. Because chronic inflammation increases with aging and inflammation plays a role in the etiology of numerous diseases that affect older populations, melatonin has the potential to be widely used particularly in older adults.

Cyclodestructive procedures for refractory glaucoma.

BACKGROUND: Cyclodestructive procedures are often used in patients with refractory glaucoma who have failed to achieve lower intraocular pressure (IOP) from filtration procedures and maximal medical therapy. Destruction of the ciliary body helps to lower IOP by reducing aqueous humor formation. Of the many types of cyclodestructive procedures, laser cyclophotocoagulation (CPC) has become the most common surgical method for reducing aqueous inflow. Options for CPC are wide-ranging: they can be performed using a neodymium:yttrium-aluminum-garnet (Nd:YAG) or diode laser and laser energy can be delivered by either the contact or non-contact method. Another cyclodestructive procedure is endoscopic cyclophotocoagulation (ECP), which the ophthalmologist can use selectively to target the ciliary epithelium and ablate ciliary body tissue. There is debate regarding which cyclodestructive method is best and how they compare to other glaucoma surgeries. OBJECTIVES: To assess the relative effectiveness and safety of cyclodestructive procedures compared with other procedures in people with refractory glaucoma of any type and to assess the relative effectiveness and safety of individual cyclodestructive procedures compared with each other. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 9); Ovid MEDLINE; Embase.com; PubMed; LILACS BIREME; ClinicalTrials.gov and the WHO ICTRP. The date of the search was 21 September 2018. SELECTION CRITERIA: We included randomized controlled trials or quasi-randomized trials in which participants underwent a secondary procedure for refractory glaucoma. We included trials with any laser type, route of administration, and laser settings. The primary comparison was any cyclodestructive procedure versus another glaucoma treatment, and the secondary comparisons were individual cyclodestructive procedures versus another cyclodestructive procedure. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed the titles and abstracts from the database searches, and after retrieving the full-text reports of those that were potentially relevant, classified the full-text articles as included or excluded. Two review authors independently extracted data from the included studies and assessed the risk of bias. Discrepancies were resolved by discussion or by consultation with a third review author when necessary. MAIN RESULTS: We included five trials reporting data for 330 eyes (326 participants). One study to had a low risk of bias for most domains and the other studies had an overall unclear risk of bias. This review includes four different comparisons: 1) ECP versus Ahmed implant, 2) micropulse CPC versus continuous-wave CPC; 3) CPC with a diode versus Nd:YAG laser; and 4) CPC with an Nd:YAG laser emitting 8J versus 4J.No study reported data for our primary outcome, change from baseline in pain severity as reported by the participant or change in number of pain medications.For our primary comparison, we included one trial that compared ECP with the Ahmed implant. At 12-month follow-up, the mean difference (MD) in IOPs between groups was -1.14 mmHg (95% confidence interval (CI) -4.21 to 1.93; 58 participants; low-certainty evidence (LCE)). At 24 months postintervention, we found very LCE suggesting that visual acuity may be better among participants in the ECP group than in the Ahmed implant group (MD -0.24 logMAR, 95% CI -0.52 to 0.04; 54 participants), and the difference in the mean number of glaucoma medications used by participants in each group was unclear (MD -0.50, 95% CI -1.17 to 0.17; 54 participants; very LCE). Reported adverse events in the ECP group (34 participants) were one case each of hypotony, phthisis bulbi, retinal detachment, and choroidal detachment; in the Ahmed implant group (34 participants) there was one case of endophthalmitis, two cases of retinal detachment, and six cases of choroidal detachment.Three types of comparisons from four included studies provided data for our secondary comparisons. In the study that compared micropulse with continuous-wave CPC, median IOP was reported to be similar between the two groups at all time points. At 18 months postintervention, the median number of IOP-lowering medications was reduced from two to one in both groups. One participant in the micropulse and two in the continuous group exhibited worsened visual acuity. One case of prolonged inflammation was seen in the micropulse group (23 participants). Seven cases of prolonged inflammation, five cases of hypotony, and one case of phthisis bulbi were seen in the continuous group (23 participants).Two studies compared CPC using a semiconductor diode versus an Nd:YAG laser. At 12 months postintervention, the MD in IOP was 1.02 mmHg (95% CI -1.49 to 3.53) in one study (LCE). The second study did not report mean IOP beyond three months of follow-up. Neither study reported the mean change in best-corrected visual acuity or number of glaucoma medications. Both studies reported hypotony as an adverse event in three participants in each study.One study compared different energy settings of the same Nd:YAG laser. At 12-month follow-up, visual acuity was unchanged or improved in 21 of 33 participants in the 8J group and 20 of 27 participants in the 4J group (risk ratio 0.86, 95% CI 0.61 to 1.21; very LCE). More participants in the 8J group reduced the number of medications taken compared with the 4J group (RR 1.49, 95% CI 0.76 to 2.91; 50 participants; very low-certainty evidence). The presence of fibrin or hyphema were seen in five participants who received 8J and none who received 4J. There was a severe anterior chamber reaction in 11 of 26 (42%) participants who received 8J of energy and 2 of 21 (10%) participants who received 4J of energy. AUTHORS' CONCLUSIONS: Evidence from five studies included in this review was inconclusive as to whether cyclodestructive procedures for refractory glaucoma result in better outcomes and fewer complications than other glaucoma treatments, and whether one type of cyclodestructive procedure is better than another. The most commonly reported adverse events across all five studies were hypotony and phthisis bulbi. Large, well-designed randomized controlled trials are needed. Patient-reported outcomes such as pain and quality of life should be considered as primary outcomes or important secondary outcomes of future trials.

Hypertensive Encephalopathy: A Case of a Male Who Bit Off His Fingers.

Although altered consciousness and other neurologic manifestations are frequently seen in hypertensive encephalopathy, behavioral and psychotic symptoms are rarely seen. We describe a patient with no previous psychiatric history who was admitted for hypertensive crisis. A few days after admission, his blood pressure remained uncontrolled and he started to exhibit episodes of confusion, agitation, and psychosis. During one particular episode, he overcame multiple staff members and physical restraints to bite off two of his fingers without any signs of pain. Brain computed tomography (CT) was notable for possible posterior cerebral and cerebellar edema. His confusion and agitation gradually resolved with successful blood pressure management. This is the first reported case of extreme, agitated behaviors and auditory hallucinations in a patient with hypertensive crisis.

Risk Factors and Long-Term Outcomes in Patients with Low Intraocular Pressure after Trabeculectomy.

PURPOSE: To examine risk factors for low intraocular pressure (IOP) after trabeculectomy and to describe long-term outcomes in these eyes. DESIGN: Retrospective case-control study. PARTICIPANTS: Cases with low IOP included all patients with IOP ≤5 mmHg on 3 or more consecutive visits 3 months or later after trabeculectomy. Control patients without low IOP after trabeculectomy were randomly selected at a 1:2 case-to-control ratio. METHODS: A case-control study was performed of patients undergoing trabeculectomy at the Stein Eye Institute. Covariates included demographics, history of cataract surgery, refractive error, number of glaucoma medications, family history of glaucoma, diabetes, hypertension, visual acuity (VA), IOP, number of sutures in the scleral flap, laser suture lysis, surgeon, and laterality of surgery. Logistic regression modeling was used to examine associations between each covariate and low IOP. Postoperative outcomes that were examined included reoperation, vision loss, and surgical failure. The time between trabeculectomy and each outcome was compared between cases and controls with Cox proportional hazards regression modeling. MAIN OUTCOME MEASURES: Low IOP after trabeculectomy, reoperation, vision loss, and surgical failure. RESULTS: Of 3659 total trabeculectomies performed by 5 surgeons between 1990 and 2013, 64 eyes had low IOP (1.7%), which were compared with 130 control eyes. Fifteen of the 64 eyes with low IOP had hypotony maculopathy (23.4%). After accounting for differences in baseline IOP, laser suture lysis was negatively correlated with low IOP after trabeculectomy (odds ratio [OR], 0.33; 95% confidence interval [CI], 0.13-0.87); surgeon was correlated with high vs. low IOP after trabeculectomy (OR, 5.32; 95% CI, 1.53-18.52). There were no statistically significant associations between low IOP and time to reoperation (hazard ratio [HR], 0.73; 95% CI, 0.32-1.68), vision loss (HR, 1.77; 95% CI, 0.81-3.88) or surgical failure (HR, 1.14; 95% CI, 0.62-2.11). In patients with low IOP, there was a higher unadjusted incidence of bleb revision in patients who had maculopathy (7.6 vs. 1.9 revisions/100 person-years; for maculopathy versus no maculopathy P = 0.008). CONCLUSIONS: The absence of laser suture lysis and surgeon are factors potentially associated with low IOP after trabeculectomy. Numeric hypotony does not necessarily represent clinical failure after trabeculectomy.

Adjunctive steroid therapy versus antibiotics alone for acute endophthalmitis after intraocular procedure.

BACKGROUND: Endophthalmitis refers to severe infection within the eye that involves the aqueous humor or vitreous humor, or both, and threatens vision. Most cases of endophthalmitis are exogenous (i.e. due to inoculation of organisms from an outside source), and most exogenous endophthalmitis is acute and occurs after an intraocular procedure. The mainstay of treatment is emergent administration of broad-spectrum intravitreous antibiotics. Due to their anti-inflammatory effects, steroids in conjunction with antibiotics have been proposed to be beneficial in endophthalmitis management. OBJECTIVES: To assess the effects of antibiotics combined with steroids versus antibiotics alone for the treatment of acute endophthalmitis following intraocular surgery or intravitreous injection. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 11), MEDLINE Ovid (1946 to 8 December 2016), Embase Ovid (1980 to 8 December 2016), LILACS (Latin American and Caribbean Health Sciences Literature Database) (1982 to 8 December 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch); searched 8 December 2016, ClinicalTrials.gov (www.clinicaltrials.gov); searched 8 December 2016, and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en); searched 8 December 2016. We did not use any date or language restrictions in the electronic searches for trials. SELECTION CRITERIA: We included randomized controlled trials comparing the effectiveness of adjunctive steroids with antibiotics alone in the management of acute, clinically diagnosed endophthalmitis following intraocular surgery or intravitreous injection. We excluded trials with participants with endogenous endophthalmitis unless outcomes were reported by source of infection. We imposed no restrictions on the method or order of administration, dose, frequency, or duration of antibiotics and steroids. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results, assessed risk of bias, and extracted data using methods expected by Cochrane. We contacted study authors to try to obtain missing information or information to clarify risk of bias. We conducted a meta-analysis for any outcomes that were reported by at least two studies. Outcomes reported from single studies were summarized in the text. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included three trials with a total of 95 randomized participants in this review and identified one ongoing trial. The studies were conducted in South Africa, India, and the Netherlands. Out of the 92 analyzed participants, 91 participants were diagnosed with endophthalmitis following cataract surgery. In the remaining participant, endophthalmitis was attributable to penetrating keratoplasty. All studies used intravitreous dexamethasone for adjunctive steroid therapy and a combination of two intravitreous antibiotics that provided gram-positive and gram-negative coverage for the antibiotic therapy. We judged one trial to be at overall low risk of bias and two studies to be at overall unclear risk of bias due to lack of reporting of study methods. None of the three trials had been registered in a clinical trial register.While none of the included studies reported the primary outcome of complete resolution of endophthalmitis as defined in our protocol, one study reported combined anatomical and functional success (i.e. proportion of participants with intraocular pressure of at least 5 mmHg and visual acuity of at least 6/120). Very low-certainty evidence suggested no difference in combined success when comparing adjunctive steroid antibiotics alone (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.80 to 1.45; 32 participants). Low-certainty evidence from two studies showed that a higher proportion of participants who received adjunctive dexamethasone had a good visual outcome (Snellen visual acuity 6/6 to 6/18) at three months compared with those in the antibiotics-alone group (RR 1.95, 95% CI 1.05 to 3.60; 60 participants). Similarly, low-certainty evidence from one study suggested that more participants in the dexamethasone group had a good visual outcome at 12 months compared to those who did not receive dexamethasone (RR 2.00, 95% CI 0.98 to 4.08; 28 participants). Investigators of one study reported improvement in visual acuity, but we could not estimate the effect of adjunctive steroid therapy because the study investigators did not provide standard deviations or standard errors. Two studies reported adverse events (retinal detachment, hypotony, proliferative vitreoretinopathy, and seclusion of pupil). The total numbers of adverse events were 8 out of 30 (26.7%) for those who received dexamethasone versus 6 out of 30 (20.0%) for those who did not. We could only perform a pooled analysis for the occurrence of retinal detachment; any difference between the two treatment groups was uncertain (RR 1.57, 95% CI 0.50 to 4.90; 60 participants) (very low-certainty evidence). No study reported intraocular pressure or cost outcomes. AUTHORS' CONCLUSIONS: Current evidence on the effectiveness of adjunctive steroid therapy versus antibiotics alone in the management of acute endophthalmitis after intraocular surgery is inadequate. We found no studies that had enrolled cases of acute endophthalmitis following intravitreous injection. A combined analysis of two studies suggests adjunctive steroids may provide a higher probability of having a good visual outcome at three months than not using adjunctive steroids. However, considering that most of the confidence intervals crossed the null and that this review was limited in scope and applicability to clinical practice, it is not possible to conclude whether the use adjunctive steroids is effective at this time. Any future trials should examine whether adjunctive steroids may be useful in certain clinical settings such as type of causative organism or etiology. These studies should include outcomes that take patient's symptoms and clinical examination into account, report outcomes in a uniform and consistent manner, and follow up at short- and long-term intervals.